Warfarin reduces the risk of stroke in atrial fibrillation by around 60%, while antiplatelet therapy is much less effective. Bleeding is, however, a notable adverse effect with warfarin. Another major drawback of warfarin is the need for frequent clotting assessment. Oral agents have been developed that directly inhibit the activity of thrombin (factor IIa), as well as drugs that directly block activated factor X (factor Xa), which is the first enzyme in the final common pathway to the activation of thrombin. These drugs have fast onset and offset of action and anticoagulation does not seem to need monitoring. These new agents for stroke prevention in atrial fibrillation are being investigated in ongoing phase III trials. In one of these trials an oral thrombin blocker has so far shown superiority to warfarin in efficacy and safety. In this Review, I address the potential of modern oral anticoagulants to improve stroke prevention in atrial fibrillation.